Treatment of hypercholesterolemia with the meso forms of 3,4-di(substituted phenyl)-3,4-hexanediol



United States Patent TREATMENT OF HYPERCHOLESTEROLEMIA WITH THE MESO FORMS OF 3,4-DI(SUBSTI- TUTED PHENYL)-3,4-HEXANEDIOL Emil Kaiser, Flossmoor, and Joseph D. Fisher, Chicago Heights, Ill., assignors to Armour Pharmaceutical Company, Chicago, Ill., a corporation of Delaware No Drawing. Filed July 26, 1965, Ser. No. 474,985 Int. Cl. A61k 27/00 U.S. Cl. 424340 9 Claims ABSTRACT OF THE DISCLOSURE For the treatment of hypercholesterolemia, there is administered parenterally to a :patient in a dosage elfective for lowering the serum cholesterol level a compound having the structure:

I. R -Qa- Q in the meso form and where R is an ethyl group and R' is a group selected from a hydrogen and a lower alkyl group.

This invention relates to lowering serum cholesterol levels.

Potent estrogens, as typified by estrone, have been employed for lowering serum cholesterol levels, but they also produce undesired estrogenic (feminizing) effects. As shown by both rat and human tests, the use of such agents is necessarily limited because of the response of the estrogen on the endocrine system. A further disadvantage, as shown by rat tests, is that such estrogens while lowering rat serum cholesterol greatly increases the rat liver cholesterol concentration in the male rat.

We have discovered that certain pinacols which do not produce the typical response of an estrogen on the endocrine system are potent agents for lowering serum cholesterol levels. Further, certain compounds are effective in lowering the serum cholesterol level without increasing the liver cholesterol concentration. Further, as shown by gas chromatography, such a compound does not produce desmosterol in the liver of rats.

Such pinacols, as will be defined by structure hereinafter, are indicated as useful as serum cholesterol lowering agents in human beings for the relief of hypercholesterolemia without producing a typical estrogen response.

In one embodiment of our invention, we employ pinacols of the structure I, meso form, where R is an ethyl group and R is a hydrogen and a lowed alkyl group preferably having from 1 to carbon atoms, such structure being as follows:

3,461,212 Patented Aug. 12, 1969 Until now, compounds of structure I were known as weak estrogens [Chemical Reviews 37, 481 (1945)] and were used as intermediates in the preparation of potent synthetic estrogens.

In the pinacols of structure I, as defined above, the meso derivatives are far more potent than the racemic mixtures. The estrogenic potency of these compounds, measured by the immature mouse assay method, is less than two percent of that of estrone, while the cholesterol lowering activity in several cases is equal to or higher than that of estrone.

Specific examples of the pinacols of structure I, meso form, are:

3,4-di(4-hydroxyphenyl) -3,4-hexanediol 3,4-di (4-methoxyphenyl -3,4-hexanediol 3,4-di (4-ethoxyphenyl -3,4-hexanediol 3,4-di(4-propyloxyphenyl)-3,4-hexanediol 3,4-di (4-allyloxyphenyl) -3,4-hexanediol 3,4-di(4-chloroallyloxyphenyl)-3,4-hexanediol 3,4-di (4-acetoxyphenyl -3,4-hexanediol 3,4-di (4-propargyloxyphenyl) -3,4-hexanediol 3,4-di(4-cyclopentyloxyphenyl)-3,4hexanediol Of the foregoing, 3,4 di(4-methoxyphenyl)-3,4-hexanediol is particularly useful in lowering serum cholesterol concentration without increasing liver cholesterol concentration.

Dosage for the treatment of hypercholesterolemia may vary widely depending upon the need of the patient, and such dosage may be on a daily basis or at intervals spaced by a week or more. Since the dosage is not critical, it may be administered and the effects measured from time to time by withdrawing blood from the patient and determining the reduction in cholesterol level, the dosage being then greatly increased or decreased in accordance with such measurement. Ordinarily, we prefer to employ on a daily basis at least about 20 mg. of the compound, and it is believed unnecessary to go above a dosage of 2 grams per day, although an increase may be required under certain conditions.

While the compounds may be administered parenterally, we prefer to have them administered orally in the form of tablets or in enteric coatings, etc. By way of example, the compound may be pressed into atabletcontaining magnesium stearate, lactose, methyl cellulose, etc.

A suitable enteric coating is formed by combining parts of cellulose acetate phthalate with 20 parts of diethyl phthalate. The mixture is dissolved in acetone and alcohol and sprayed on the treating compound to about 5 to 10 percent of the weight of the tablet.

Specific examples which are illustrative of the invention are set out as follows:

EXAMPLE I Test compounds, as set out in the following table, were administered to male rats weighing 200 to 250 grams and having hypercholesterolemia, the administration being orally for four days and the treating compound being in sesame oil. The autopsy wasorrthe-fifth day andthe liver and serum were assayed for cholesterol concentration. The results were set out in the following table:

TABLE I.RAI SERUM CHOLESTEROL LOWERING ACTIVITY OF COMPOUNDS STRUCTURE I Serum cholesterol lowering Estrogenie activity, activity, Compound percent percent Estrone 100 100 3,4-di(4=hydroxyphenyl)-3,-hexanediol, meso form Approx. 120 Approx. 0. 3,4-di(4-hydroxyphenyl)-3,4-hexanodiol racemic mixture 1 3,4-di(4-methoxyphenyl)-3,4hexanediol meso form Approx. 140 Approx, 1, 0 3,4-di(4-ethoxypl1enyl)-3,4 hexanediol meso form Approx. 110 1, 0 3,4-di(4-propyloxyphenyl)-3,4-hexanediol meso form Approx. 25 g 0 3,4-di(4-allyloxyphenyl)-3,4-hexanediol meso form Approx. 50 2, 0 3,4-di( l-chloroallyloxyphenyl) hexanediol, meso form... Approx. 50 3,4-di(4-acetoxyphenyl)-3,4-he. ne-

diol meso form Approx. 20-50 2 3,4-di(4-acetoxyphenyl) 3A-hexanedlol, racemle niixturiafluiyzuu Approx. 8. 0 3 4-di 4- ro orgy oxyp ieny hexhn di l meso form Approx. 30. 0 2 2,3-dl (4-hyd roxyphenyl)-2,3-butanediol 2. 0 3,4-di(-cyclopentyloxyphenyl)- 3,4-hexanediol meso form Approx. 100

EXAMPLE II Tests were made for comparison of rat serum cholesterol concentration and rat liver cholesterol concentration caused by treatment with estrone and with 3,4-di(4-me thoxyphenyl)-3,4-hexanediol (Structure I, R=ethyl;

R :methyl) Assay conditions:

(1) 200-250 g. male rats (2) Oral administration of test compounds in sesame oil for 4 days (3) Autopsy on fifth day, assay for liver and serum cho- EXAMPLE III Tests were made in the manner described in Example I to determine serum cholesterol lowering activity, with the results set out in the following table:

TAB LE III Response, mg. percent of Compound Dose, rug/100 serum chog. lesterol Estrono 0. 004 54 0. 04 43 0. 4 32 3, 4-dl-(4-hydroxyphenyD-3, 4-hexane 0. 004 70 die! (raeemate). 060: 68 68 3, 4-dl (4-hydroxyphenyD-3, 4-hexane- 0. 004 52 diol (meso). 0. 04 40 0. 4 21 3, 4-di (t-methoxyphenyl) 3, 4-hexane- 0. 002 57 diol (meso). 0.02 41 0.2 35 3, 4- di (4-ethoxyphenyl) 3, t-hexane- 0. 003 53 diol (meso). 0. 03 42 0.3 33 3, 4-di- (tpropyloxyphenyl) 3, i-hex- 0. 04 62 ane dlol (meso). 0. 4 48 4. 0 20 4 EXAMPLE 1v Toxicity tests were made on adult males. Ten mg. of 3,4-di(4-methoxyphenyl)-3,4-hexanediol meso form were combined with 48 mg. of lactose, 10 mg. of microcrystalline cellulose (Avicel) and 2 mg. of magnesium stearate, the pressed tablet weighing mg.

Tablets were administered orally to human male patients at rates of from 10 to 200 mg. per day of the compound 3,4-di(4-methoxyphenyl)-3,4-hexanediol meso form, the dosage of 10 mg. being for two weeks, 20 mg. for two weeks, 40 mg. for two weeks, mg. for two weeks, and 200 mg. for two weeks. No toxic effects were observed, and on the basis of the rat tests, it is believed to be indicated that up to 2 grams and above can be administered to patients without untoward toxic effects. Since the male patients had a normal cholesterolemic condition, the effect of lowering the serum cholesterol level was not observed.

While in the foregoing specification we have set forth specific procedure and ingredients in considerable detail for the purpose of illustrating the invention, it will be understood that such detail or details may be varied widely by those skilled in the art without departing from the spirit of our invention.

We claim:

1. In the treatment of hypercholesterolemia, the step of administering parenterally to a patient a dosage effective for lowering serum cholesterol levels of a compound having the structure:

III R -QH-Q- OH OH in the meso form and where R is ethyl and R is hydrogen or lower alkyl.

2. In the treatment of hypercholesterolemia, the step of administering orally to a patient a dosage effective for lowering serum cholesterol levels of a compound having the structure:

in the meso form and where R is ethyl and R is hydrogen or alkyl having 1 to 5 carbon atoms.

3. The process of claim 2 in which the dosage is one effective for lowering the serum cholesterol level and constituting at least about 20 mg. on a daily basis.

4. The process of claim 3 in which the dosage is in an amount effective for lowering the serum cholesterol level and is in an amount of from about 20 mg. to 2 grams.

5. In the treatment of hypercholesterolemia, the step of administering orally to a patient a dose in an amount effective for lowering the serum cholesterol level of 3,4-di(4- methoxyphenyl)-3,4-hexanediol meso form.

6. In the treatment of hypercholesterolemia, the step of administering orally to a patient a dose in an amount effective for lowering the serum cholesterol level of 3,4- di(4-hydroxyphenyl)-3,4-hexanediol meso form.

7. In the treatment of hypercholesterolemia, the step of administering orally to a patient a dose in an amount effective for lowering the serum cholesterol level of 3,4- di(4-ethoxyphenyl)-3,4-hexanediol meso form.

8. In the treatment of hypercholesterolemia, the step of administering orally to a patient a dosage effective for lowering serum cholesterol levels of a compound having the structure:

in the meso form and where R is ethyl and R is hydrogen or alkyl, the compound being combined with lactose,

methyl cellulose and magnesium stearate in tablet form for oral administration.

9. In the treatment of hypercholesterolemia, the step of administering orally to a patient a dosage efiective for lowering serum cholesterol levels of a compound having the structure:

in the meso form and where R is ethyl and R is hydrogen or alkyl, the compound being provided with an enteric coating which releases the compound when it reaches the intestinal tract.

References Cited Malinow et al., J. Lab. and Clin. Med., November 1962, pp. 740-746.

ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assistant Examiner US. Cl. X.R. 424345 

